1. Field of the Invention
The invention relates to improved process for preparation of an amorphous form of the hemi-calcium salt of atorvastatin in stable form. The present invention also provides the amorphous form of hemi-calcium salt of atorvastatin with high purity. Atorvastatin calcium is known as hemi-calcium salt of (3R, 5R) 7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid of formula (I).

2. Background Art
Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.
Atorvastatin (formula I) is manufactured according to published patents (U.S. Pat. Nos. 4,681,893; 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,273,995; 5,397,792; 5,342,952) and its calcium salt is usually made from sodium salt of (3R,5R)-7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid and a suitable, water soluble calcium salt, preferably from calcium acetate or chloride. Atorvastatin is usually prepared as the calcium salt since this enables atorvastatin to be conveniently formulated in pharmaceutical formulations, for example, in tablets, capsules, powders and the like for oral administration.
The starting sodium salt of (3R,5R)-7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid may be obtained from the said acid, which is normally obtained from (3R,5R) tert-butyl (6-{2-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]dioxane-4-yl)-acetate (formula II).

This key intermediate is converted to the sodium salt of the respective acid first by mixing with hydrochloric acid and, later on, with a large excess of sodium hydroxide, which is, however, accompanied with a large amount of excess hydroxide and also of sodium chloride. Acidification followed by extraction then affords a solution of the respective acid (formula III) without any inorganic impurities. Thus obtained acid is then converted to the respective lactone (formula IV), which can be purified by crystallization, and the purified lactone is then converted to the sodium salt by mixing with an equivalent of sodium hydroxide; an excess cannot be used as it would form, with the calcium salt, calcium hydroxide in the next step that could not be fully removed from the product in the follow up process steps according to the above patents. However, when an equivalent of the hydroxide is used the reaction is time consuming and it has to be monitored by HPLC. Another disadvantage of this process is loss of approximately 20% of the yield.

Atorvastatin calcium can exist in amorphous form or in various known crystalline forms like Form I, Form II, Form III and Form IV, which are disclosed in International Publications Nos. WO 97/3958 (U.S. Pat. No. 6,121,461) and WO 97/3959 (U.S. Pat. No. 5,969,156). It is known that the amorphous forms of a number of pharmaceutical substances exhibit different dissolution characteristics and bioavailability patterns compared to the crystalline forms (Konno T., Chem. Pharm. Bull., 1990, 38:2003-2007). For some therapeutic indications the bioavailability is one of the key parameters determining the form of the substance to be used in a pharmaceutical formulation. Since processes for the crystallization and the preparation, respectively, of the amorphous substance are sometimes difficult, and sometimes afford amorphous-crystalline mixtures, that is, a crystalline form instead of an amorphous form, there is a constant need for processes which enable the preparation of a non-crystalline form without simultaneous formulation of crystalline forms, that is, which will enable the conversion of the crystalline form into the non-crystalline form.
Atorvastatin calcium is a substance, which is very slightly water-soluble, and it has been found that the crystalline forms are less readily soluble than the amorphous form, which may cause problems in the bioavailability of atorvastatin in the body. It has been found that the production of amorphous atorvastatin calcium according to the previously disclosed processes was not consistently reproducible, and therefore a process has been developed for converting the crystalline forms of atorvastatin calcium (formed in the synthesis of atorvastatin) to the amorphous form. The process is described in International Publication No. WO 97/3960 (U.S. Pat. No. 6,087,511) and comprises dissolving a crystalline form of atorvastatin calcium in a non-hydroxylic solvent and removing the solvent to afford amorphous atorvastatin calcium. The preferred non-hydroxylic solvent is selected from the group consisting of tetrahydrofuran and a mixture of tetrahydrofuran and toluene. The disadvantage of the above process is primarily use of non-nature-friendly solvents.
A similar process is described in International Publication No. WO 00/71116 and comprises dissolving the crystalline form of atorvastatin calcium in a non-hydroxylic solvent, such as, for example, tetrahydrofuran. To the solution of atorvastatin calcium is added a non-polar organic solvent, or the solution of atorvastatin calcium is added to a non-polar organic solvent, to allow atorvastatin calcium to precipitate. The formed precipitate is filtered off.
Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. For a general review of polymorphs and the pharmaceutical applications of polymorphs see G. M. Wall, Pharm Manuf. 3, 33 (1986); J. K. Haleblian and W. McCrone, J. Pharm. Sci., 58, 911 (1969); and J. K. Haleblian, J. Pharm. Sci., 64, 1269 (1975), all of which are incorporated herein by reference.
U.S. Pat. No. 7,208,608 B2 discloses a method of manufacturing an amorphous form of the hemi-calcium salt of (3R,5R) 7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyr-rol-1-yl]-3,5-dihydroxyheptanoic acid, in which (3R,5R)-7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxy heptanoic acid or its salt with a cation M+ wherein M+ is either a cation of an alkali metal or an ammonium cation of formula RnN(+)H(4-n) wherein R is lower C1-C5 alkyl, n may reach values ranging between 0 and 3, is, without isolating the intermediate in the form of the hemi-calcium salt or of another salt, acid or lactone, converted, in a solution, by the treatment with the calcium salt or calcium hydroxide, or a calcium C1-C5 alcoholate, to the hemi-calcium salt, and the latter is precipitated with a C1-C5 hydrocarbon or dialkylether of formula R1OR2, wherein each of R1 and R2 is a C1-C5 alkyl group. The starting acid or its salt is prepared starting from (3R,5R) tert-butyl (6-{2-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]dioxane-4-yl)acetate.
U.S. Pat. No. 6,750,353 B2 provides the process for preparation of pharmaceutically acceptable atorvastatin salts in non-crystalline form, which comprises of providing a solution in a non-hydroxylic solvent like tetrahydrofuran of compound of formula II, shown below:
followed by deprotection of the hydroxy and acid protecting group and adding a solvent which is slightly miscible or immiscible with water and in which the pharmaceutically acceptable salt is insoluble or practically insoluble like hexane, heptane, cyclohexane, ether and diisopropyl ether, etc., further followed by neutralizing the aqueous phase and converting atorvastatin into pharmaceutically acceptable salt.
EP 1,659,110 A1 claims the process for production of amorphous atorvastatin calcium and stabilized, amorphous atorvastatin calcium. The process provided for production of stabilized amorphous atorvastatin calcium comprises of dissolving crystalline atorvastatin calcium and an antioxidant in a solvent and adding the solution to an antisolvent, and obtaining stabilized amorphous atorvastatin calcium. The stabilized amorphous form of atorvastatin calcium is claimed containing not more than 0.2% of various impurities by HPLC and 0.5% of total impurities. Also, the relative stability after 3 months at 25° C./60% RH is provided.
U.S. Pat. No. 7,208,608 B2 of M/s Zentiva provides the process for preparation of atorvastatin calcium in amorphous form. However, the patent clearly discloses the extraction of sodium salt with ethyl acetate or crystallization of sodium salt of atorvastatin in ethanol followed by treatment with ethyl acetate, which may results in higher atorvastatin lactone content.
Further, atorvastatin calcium obtained as per process in U.S. Pat. No. '608 B2 suffers the disadvantage that the product required prolonged drying conditions to remove residual ethyl acetate or hydrocarbon solvents. The product does not meet the residual solvent requirements as per ICH limits. Hydrocarbons like cyclohexane, hexane etc. are class 2 solvents having limits of 3880 ppm and 290 ppm, respectively. It is extremely difficult to obtain residual solvents below these limits by the process as per U.S. Pat. No. '608 B2.
Thus, there is still a need to provide a very cost effective and industrially viable process for large-scale productions for the preparation of stabilized amorphous atorvastatin calcium.